The present invention relates to a method for ceasing smoking and substance addiction-related behaviors. In particular, the present invention includes a method for altering familiar sensations and ritualistic behaviors associated with smoking and substance addiction by peripheral administration of a Clostridial toxin to bodily locations on or in the mouth, nose and fingers, or in the vicinity of such locations which come into contact with a smoking tool or addictive substance.
Smoking is a practice where a substance, most commonly tobacco, is burned and the smoke tasted or inhaled. This is the primary practiced route of administration for recreational drug use, as combustion releases the active substances in drugs, such as nicotine or tetrahydrocannabinol (THC), and makes them available for absorption through the lungs. An estimated 43.4 million people or 19.8% of all adults (aged 18 years and older) in the United States currently smoke cigarettes (Centers for Disease Control and Prevention website, 2009). Most tobacco smokers begin during adolescence or early adulthood. Smoking contributes to numerous medical problems and an early death in approximately one-third of smokers. Although personality and social factors may make people likely to smoke, the actual habit is a function of operant conditioning (Covino and Bottari. Hypnosis, Behavioral Theory, and Smoking Cessation. Journal of Dental Education 2001; 65:340-347).
During the early stages, smoking provides pleasurable sensations because of its action on the dopamine system and thus serves as a source of positive reinforcement (Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988; 85:5274-5278). After an individual has smoked for many years, the avoidance of withdrawal symptoms (e.g., irritability, anxiety, difficulty concentrating, increased appetite) and negative reinforcement become the key motivations. There is also a substantial psychological aspect to smoking. People who smoke tend to rationalize their behavior, believing that smoking provides comfort, relieving stress for example.
In general, substance addiction is a pathological condition involving a compulsion to continue using the substance, whether it be chewing tobacco or recreational drugs such as marijuana or cocaine, despite the negative consequences. Like tobacco smoking, other substance addictions involve not only a physical component, most often a chemical dependency, but also a substantial psychological component accompanied by ritualistic behavior, such as those involved in the act of smoking or sniffing the addictive substance.
Among current U.S. adult smokers, 40% have stopped smoking for at least one day within a twelve month time period because they were trying to quit smoking. Because smoking (e.g., tobacco or other recreational drugs) is very addictive, both physically and psychologically, most smoking cessation methods have poor success rates, and quitting often requires repeated intervention (Centers for Disease Control and Prevention website, 2009). Various methods and products are used in attempts to quit smoking, including nicotine gum, inhaler, nasal spray, lozenge, patch, counseling, and prescription normicotine medications, such as bubropion SR (Zyban®) and varenicline tartrate (Chantix®) (Fiore M C, et al. Treating Tobacoo Use and Dependence: 2008 Update—Clinical Practice Guidelines, 2008 [accessed 2009 Feb. 6]; U.S. Food and Drug Administration. The FRD Approves New Drug for Smoking Cessation. FDA Consumer, July-August 2006 [accessed 2009 Feb. 6]).
Many current treatments may also fail because they do not address all aspects of the substance addiction, particularly the psychological aspect. Not only do substance addicts form a chemical dependency on the active drug, but they also form a psychological dependency based on familiarity and repetitive motor activity, including for example the familiarity of holding a cigarette (tobacco or marijuana) in one's hands, flicking the cigarette, drawing it to one's mouth, and holding the cigarette between one's lips. It may be this habitual/ritualistic behavior and sense of familiarity that the majority of current treatments fail to address.
At present, botulinum neurotoxins are being used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. Botulinum neurotoxin serotype A was approved in 1989 by the U.S. Food and Drug Administration for the treatment of essential blepharospasm, strabismus and hemifacial spasm in patients over the age of twelve. In 2000, the FDA approved for the treatment of cervical dystonia commercial preparations of serotype A and serotype B botulinum neurotoxin, and in 2002 the FDA approved for the cosmetic treatment of certain hyperkinetic (glabellar) facial wrinkles a serotype A botulinum neurotoxin. In 2004, botulinum neurotoxin was approved by the FDA for the treatment of hyperhidrosis. Non-FDA approved uses include hemifacial spasm, spasmodic torticollis, oromandibular dystonia, spasmodic dysphonia and other dystonias, tremor, myofascial pain, temporomandibular joint dysfunction, migraine, and spasticity.
The success of botulinum neurotxin serotype A to treat a variety of clinical conditions has led to interest in other botulinum neurotoxin serotypes. A botulinum neurotoxin serotype B (BT-B) preparation (MyoBloc®) is available from Solstice Neurosciences of Malvern, Pa.
Similar therapeutic effects are seen after about 150-200 mouse units of Botox® or about 500-750 mouse units of Dysport®. This indicates a conversion factor for Botox® to BT-B in the order of 40-70 and for Dysport® to BT-B of 10-20. (See Dressler, Botulium Toxin Type B: Where Do We Stand?, 114 Eur Neurol, 46:113-114 (2001)).
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum neurotoxin. To date, seven immunologically distinct botulinum neurotoxins have been characterized: serotypes A, B, C1, D, E, F, and G. Of these, botulinum neurotoxin serotype A is recognized as one of the most lethal naturally occurring agents.
It is postulated that the botulinum neurotoxins bind with high affinity to cholinergic motor neurons, are transferred into the neuron and effectuate blockade of the presynaptic release of acetylcholine. All of the botulinum neurotoxin serotypes are purported to inhibit release of acetylcholine at the neuromuscular junction, and they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. It is believed that differences in the site of inhibition are responsible for the relative potency and/or duration of action of the various botulinum toxin serotypes.
Despite the apparent difference in serotype binding, it is thought that the mechanism of botulinum activity for each serotype is similar and involves at least three steps. First, the toxin binds to the presynaptic membrane of a target cell. Second, the toxin enters the plasma membrane of the effected cell wherein an endosome is formed. The toxin is then translocated through the endosomal membrane into the cytosol. Third, the botulinum neurotoxin appears to reduce a synaptosomal-associated protein (SNAP) disulfide bond resulting in disruption in zinc (Zn++) endopeptidase activity, which selectively cleaves proteins essential for recognition and docking of neurotransmitter-containing vesicles with the cytoplasmic surface of the plasma membrane, and fusion of the vesicles with the plasma membrane.
The molecular weight of the botulinum neurotoxin protein molecule, for all seven of the known botulinum neurotoxin serotypes, is about 150 kD. Interestingly, the botulinum neurotoxins are released by Clostridial bacterium as complexes comprising the 150 kD botulinum neurotoxin protein molecule along with associated non-toxic proteins. Thus, the botulinum neurotoxin serotype A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum neurotoxin serotypes B and C1 are produced as only a 500 kD complex. Botulinum neurotoxin serotype D is produced as both 300 kD and 500 kD complexes. Finally, botulinum neurotoxin serotypes E and F are produced as only approximately 300 kD complexes. The complexes (i.e., molecular weight greater than about 150 kD) are believed to contain anon-toxic hemagglutinin protein and a non-toxic non-hemagglutinin protein. These two non-toxic proteins (which along with the botulinum neurotoxin molecule can comprise the relevant neurotoxin complex) may act to provide stability against denaturation to the botulinum neurotoxin molecule and protection against digestive acids when toxin is ingested.
All the botulinum neurotoxin serotypes are made by Clostridium botulinum bacteria as inactive single chain proteins which must be cleaved or nicked by proteases to become neuroactive. The bacterial strains that make botulinum neurotoxin serotypes A and G possess endogenous proteases and serotypes A and G can therefore be recovered from bacterial cultures in predominantly their active form. By contrast, botulinum neurotoxin serotypes C1, D, and E are synthesized by nonproteolytic strains and are therefore typically inactivated when recovered from culture. Serotypes B and F are produced by both proteolytic and nonproteolytic strains and therefore can be recovered in either the active or inactive form. However, even the proteolytic strains that produce, for example, the botulinum neurotoxin type B serotype only cleave a portion of the toxin produced. The exact proportion of nicked to unnicked molecules depends on the length of incubation and the temperature of the culture. Therefore, a certain percentage of any preparation of, for example, the botulinum neurotoxin serotype B is likely to be inactive, possibly accounting for a lower potency of botulinum neurotoxin serotype B as compared to botulinum neurotoxin serotype A. The presence of inactive botulinum neurotoxin molecules in a clinical preparation will contribute to the overall protein load of the preparation, which has been linked to increased antigenicity, without contributing to its clinical efficacy.
In vitro studies have indicated that botulinum neurotoxin inhibits potassium cation-induced release of both acetylcholine and norepinephrine from primary cell cultures of brainstem tissue. Additionally, it has been reported that botulinum neurotoxin inhibits the evoked release of both glycine and glutamate in primary cultures of spinal cord neurons and that in brain synaptosome preparations, botulinum neurotoxin inhibits the release of each of the neurotransmitters acetylcholine, dopamine, norepinephrine, CGRP and glutamate.
High quality crystalline botulinum neurotoxin serotype A can be produced from the Hall A strain of Clostridium botulinum with characteristics of 3×107 U/mg, an A260/A278 of less than 0.60 and a distinct pattern of banding on gel electrophoresis. The known Shantz process can be used to obtain crystalline botulinum neurotoxin serotype A, as set forth in Shantz, et al. (See Shantz, et al. Properties and use of Botulinum Toxin and Other Microbial Neurotoxins in Medicine, Microbiol Rev. 56: 80-99 (1992)). Generally, the botulinum neurotoxin serotype A complex may be isolated and purified from an anaerobic fermentation by cultivating botulinum neurotoxin serotype A in a suitable medium. Raw toxin may be harvested by precipitation with sulfuric acid and concentrated by ultramicrofiltration. Purification may be carried out by dissolving the acid precipitate in calcium chloride. The toxin may then be precipitated with cold ethanol, dissolved in sodium phosphate buffer and centrifuged. Upon drying there may then be an approximately 900 kD crystalline botulinum neurotoxin serotype A complex with a specific potency of 3×107 LD50 U/mg or greater (LD, lethal dose). This known process can also be used, upon separation out of the non-toxic proteins, to obtain pure botulinum neurotoxins, such as for example: (1) purified botulinum toxin type A with an approximately 150 kD molecular weight with a specific potency of 1−2×108 LD50 U/mg or greater; (2) purified botulinum neurotoxin serotype B with an approximately 156 kD molecular weight with a specific potency of 1−2×108 LD50 U/mg or greater; and (3) purified botulinum neurotoxin serotype F with an approximately 155 kD molecular weight with a specific potency of 1−2×107 LD50 U/mg or greater.
Already prepared and purified botulinum neurotoxins and toxin complexes suitable for preparing pharmaceutical formulations can be obtained from List Biological Laboratories, Inc., Campbell, Calif.; the Centre for Applied Microbiology and Research, Porton Down, U.K.; Wako (Osaka, Japan), as well as from Sigma Chemicals of St. Louis, Mo.
Two commercially available botulinum type A preparations for use in humans are BOTOX® available from Allergan, Inc., of Irvine, Calif., and Dysport® available from Beaufour Ipsen, Porton Down, England. BOTOX® consists of a purified botulinum neurotxin serotype A complex, albumin and sodium chloride packaged in sterile, vacuum-dried form.
Clinical effects of peripheral administration of botulinum neurotoxin serotype A are typically observed within 24-48 hours of administration and sometimes within a few hours. When used to induce muscle paralysis, symptomatic relief from, for example, a single intramuscular injection of botulinum toxin type A may last approximately three months; however, under certain circumstances effects have been known to last for several years.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.